Abstracts

Rationale: Loss-of-function variants in SYNGAP1 are associated with a neurodevelopmental spectrum that includes intellectual disability (ID) and epilepsy. We sought to analyze the phenotypes and genotype-phenotype relationships of the largest known cohort of patients with SYNGAP1 variants to date.

Methods: Data from individuals with SYNGAP1 variants were ascertained from Invitae’s Ciitizen database, a platform that collects designated record sets and harmonizes extracted data using standard terminologies. We assessed variant pathogenicity using American College of Medical Genetics and Genomics criteria. We conducted a retrospective analysis, using descriptive statistics, for individuals with pathogenic or likely pathogenic variants.

Results: We determined that 88 participants had pathogenic or likely pathogenic variants in SYNGAP1, and most were truncating variants (N=64, 72.3%). Eight variants were recurrent within the cohort. The average age of diagnosis of SYNGAP1-related disorder was 6.4 years (range, 1-64 years). Global developmental delay was diagnosed in 82 (93%) individuals at an average age of 24 months. Epilepsy was diagnosed in 77 (88%) individuals at an average age of 40 months. Autistic features/autism spectrum disorder (ASD) was diagnosed in 60 (68%) participants and ID in 47 (53%). A diagnosis of global developmental delay preceded the epilepsy diagnosis in 51 (58%) of individuals, with an average duration of 24 months between the global developmental delay and epilepsy diagnoses. The frequency of global developmental delay, epilepsy, ASD, and ID did not differ between the types of variants (truncating, missense, intronic, and copy number variants) or by variant location. Individuals with one of the recurrent variants had no difference in the frequency of associated global developmental delay, epilepsy, ASD, or ID compared to the total cohort. _x000D_
Among those with epilepsy, the most frequent seizure type was absence seizures with or without eyelid myoclonia (n=69, 89.6%), followed by atonic (n=36, 46%), myoclonic (n=13, 17%), and tonic-clonic (n=13, 17%). Status epilepticus was reported in 6 individuals. The average number of anti-seizure medications (ASMs) trialed per participant was 3.2, the most frequent being levetiracetam (N=43, 56%), lamotrigine (N=39, 49%), clobazam (N=39, 51%), and valproate (N=37, 48%). The most frequent medications with ongoing use were lamotrigine (N=26, 34%) and clobazam (N=28, 36%).

Conclusions: Our retrospective analysis of database-derived medical records data regarding SYNGAP1-related disorder reveal an overall picture of developmental delay and ultimately intellectual disability as often the first diagnosis, followed by onset of epilepsy in the majority of individuals. These results can inform development of targeted clinical trial outcomes and highlight a window of opportunity for prevention or early identification of seizures between the diagnosis of developmental delay and the onset of epilepsy.

Funding: SynGAP Research Fund